Sulfonamides, antifolates, and fluoroquinolones (Fitz) Flashcards
Sulfonamides are competitive inhibitors of ___
dihydropteroate synthase - an essential enzyme in the folate biosynthesis pathway of many bacteria; no production of dihydropteroate or dihydrofolate
This drug is the main sulfonamide in clinical use today and used in fixed dose combos with Trimethoprim
sulfamethoxazole
what does trimethoprim inhibit?
dihydrofolate reductase –> no production of tetrahydrofolate
list the site of infx and condition associated with H influenza with the use of Trimethoprim-Sulfamethoxazole combo:
H influenza –> resp tract, sinusitis
others include:
-Pneumocystis jiroveci –> lung, pneumonia
What are the resistance mechanisms of bacteria against sulfamethoxazole?
- mutation of dihydropteroate synthase
- enhanced acquisition of PABA
what are the resistance mechanisms of bacteria against Trimethoprim?
- mutation of DHFR
- overexpression of DHFR
What types of pathogens are resistant to trimethoprim-sulfamethoxazole?
Folic acid auxotrophs are naturally resistant (E faecalis)
MRSA is variably susceptible
List the main therapeutic uses for sulfamethoxazole/trimethoprim and/or sulfonamides in general:
- uncomplicated UTI
- tx and prevention of Pneumocystis carinii pneumonia (PCP) in HIV pts
- toxoplasmosis in immunosuppressed pts
List some adverse effects of sulfonamides:
- hypersensitivity (Stevens-Johnson): occurs with TMP-SMX more than other sulfa drugs
- kernicterus: neonatal encephalopathy, displaces bilirubin from albumin and get poor bilirubin clearance
- hemolytic anemia (attn: pts with X-linked G6PD-deficiency)
When is SMX contraindicated in the pregnant/post-pregnant mother?
near term and in breast fed neonate (liver immaturity)
In individuals with G6PD deficiency, sulfonamides can cause oxidative stress on erythrocytes. These pts generate insufficient NADPH and an excess of ___
GSSG and H2O2 –> cause Hb denaturation, acute hemolysis, and red cell loss
what are adverse effects of trimethoprim?
birth defects d/t folate deficiency, such as CV defects and oral clefts
Careful at the 2-3 month period/1st trimester
what is the MOA of fluoroquinolones?
inhibit DNA gyrase (topoisomerase II) and topoisomerase IV
Which enzymes are inhibited by fluoroquinolones and what bacteria type are their targets?
inhibition of DNA gyrase is more significant in gram -
inhibition of topoisomerase IV is more significant in gram +
how can fluoroquinolone resistance develop?
- mutation of DNA gyrase/topoisomerase
- cell membrane efflux mechanisms
- -decreased number of porins -Multi drug resistance *
List the more common 2nd, 3rd, and 4th generation fluoroquinolones:
2nd–> Ciprofloxacin
3rd–> Levofloxacin
4th–> Moxifloxacin
What are Gen 2/3/4 fluoroquinolones effective against?
- range of gram - such as H influenza, Moraxela catarrhalis
- Tx of osteomyelitis d/t gram - orgs (fluoroquinolones have high bone penetration)
- Also active against several atypical orgs that cause pneumonia
which atypical orgs is ciprofloxacin most effective against? Gram + ?
atypical –> mycoplasma, chlamydia, Mycobacteria, legionella
Gram + –> Bacillus anthracis
which atypical orgs is levofloxacin most effective against? Gram + ?
atypical –> More active vs Mycoplasma, chlamydia, legionella
Gram + –> Some gram + cocci, e.g., S pneumoniae
which atypical orgs is Moxifloxacin most effective against? Gram + ?
atypical –> More active vs mycoplasma, chlamydia, legionella
Gram + –> enhanced gram + cocci and bacilli, and anaerobes
Has no activity against P aeruginosa
Which FQ’s are indicated for community acquired pneumonia?
Ciprofloxacin, levofloxacin, Moxifloxacin, Gemifloxacin
Which FQ’s are indicated for acute exacerbation of chronic bronchitis?
levofloxacin, moxifloxacin, gemifloxacin
which FQ’s are indicated for acute bacterial rhino sinusitis?
ciprofloxacin, levofloxacin, moxifloxacin
which FQ’s are indicated for nosocomial pneumonia?
ciprofloxacin and levofloxacin
What are some distinctive uses for ciprofloxacin?
ANTHRAX, osteomyelitis, febrile neutropenia, typhoid fever, abdominal infx
what are some distinctive uses for moxifloxacin?
complicated intra-abdominal infx (anaerobic) plus metronidazole
what can impair the oral absorption and lower bioavailability of all FQ’s?
antacids
milk, yogurt
vitamin mineral supps with Fe or Zn
take separately, not together
What are adverse effects of FQ’s?
CT problems –> Peds warning:cartilage erosion, arthropy; Geriatrics warning: Tendon rupture, tendonitis
Phototoxicity
Prolonged QTc interval –> slows repolarization
Potential risk of peripheral neuropathy taken PO or injection
what administered route of FQ’s do not show adverse effects on cartilage development in peds pts?
Topically applied FQ’s –> eye or ear drops
This drug combo can be used for opportunistic infx such as toxoplasmosis; pneumocystis jiroveci
Sulfamethoxazole and Trimethoprim
what types of pts have higher incidence of adverse effects with the use of sulfa drugs?
AIDS pts (higher doses)
What is the drug of choice if you suspect anthrax exposure?
ciprofloxacin
what is the drug of choice in an immunocompromised pt who has Pneumocystis jiroveci pneumonia?
Trimethoprim-sulfamethoxazole
What is the drug of choice in an HIV-infected pt with a CD4 count of less than 100 uL who has toxoplasmosis?
trimethoprim-sulfamethoxazole
